Chiral catalysis. This is a relatively brief look at some classic examples of chiral catalysis in organic synthesis. It gives a quick overview but does not go into any detail.

1. LECTURE TWO
chiral catalysis
©ystenes@flickr
1

2. chiral
product
chiral
reagent
substrate
(achiral)
chiral
catalyst
chiral
reagent
substrate
(achiral)
chiral
product
chiral
catalysis
2

3. ©mugley@flickr
H
CO2H
NHAc
MeO
AcO
H2(g)
[((S)-DIPAMP)RhL2]
L=solvent MeO
AcO
CO2H
H NHAc
H H
95% ee
(S,S)-DIPAMP
P P
OMe
MeO
industrial
production
L-DOPA
3

4. productionL-DOPA
P P
OMe
MeO
O
MeN
H
HO2C
Ar
Rh
L L
P P
OMe
MeO
Rh O
MeN
H
HO2C
Ar
industrial
4

5. Ph
CO2Me
NHCOMe
P
Rh
P
S S
PhAr
ArPh
+ kminor : kmajor 573 : 1
Rh
H
N CO2Me
OPhP
P
fast
major
Rh
H
NMeO2C
OPh P
P
fast
minor
Rh
H
NMeO2C
OPh P
H
H
P
Rh
H
P
O
P
SHN
Ph
MeO2C
Ph
HMeOCHN
MeO2C
major
H2 slow
RDS
kminor
Rh
H
N CO2Me
OPhP
H
H
P
Rh
H
P
O
P
S NH
Ph
CO2Me
Ph
H NHCOMe
CO2Me
minor
H2 slow
RDS
kmajor
mechanismlock & keyanti
one of many mechanisms for hydrogenation
apologies for old (>10 years) ChemDraw scheme
5

6. ©AJC1@flickr
N
F
N
OMeN
O
CO2H
levofloxacin
Proc. Natl. Acad. Sci. USA, 2004, 101, 5356
& Tetrahedron Lett., 1991, 32, 4163
6

7. O
OH OH
H OH
Ph2
P
P
Ph2
RuCl2
H2
97%
91%ee
in
total synthesis
chiral catalysis
7

8. P P
Cl
H
Ru
OH
O
proposed
transition state
cause
hindrance
equatorial
8

9. ©2004 by National Academy of Sciences
proposed
transition state
9

10. ©Calamity Meg@flickr
O
N•HCl
CF3
(R)-fluoxetine
J. Am. Chem. Soc., 2000, 122, 6510
10

11. Ph
O
Me2N
SM : catalyst
10,000 : 1
H2
96%
97.5%ee
Ph
Me2N
H OH
Ar2
P
P
Ar2
Ru
Cl
Cl
N
H2
H2
N
iPr
H
OMe
OMe
Ar = 3,5-Me2C6H3
in
total synthesischiral catalysis
11

12. functionalised
H
Ru
N
H
O
C
RSRLnon
ketone
12

13. OMeO
MeO
catalyst (10%)
BH3•THF
MeO
MeO
OHH
93% eeN
B O
H
Ph
Ph
Me
catalyst
reductionenantioselectivecatalytic
reduction
CBS
13

14. Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
RL RS
H OH
N
B O
H
Ph
Ph
Me
H3B
RL RS
O
N
B O
H
Ph
Ph
Me
BH3•THF
mechanismof
reductionCBS
14

15. mechanismof
reductionCBS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
RL RS
H OH
N
B O
H
Ph
Ph
Me
H3B
RL RS
O
N
B O
H
Ph
Ph
Me
BH3•THF
15

16. N
O
F
OH
OH
F
ezetimibe
J. Med. Chem., 2004, 47, 1
16

17. F
O
N
O
O
Ph
catalyst (10%)
BH3•THF
N
B O
H
Ph
Ph
Me
catalyst
F
N
O
O
Ph
HHO
>95%
>99:1 dr
in
total synthesis
chiral catalysis
N
O
F
OH
F
HO H
17

18. OH
(+)-DIPT,
Ti(Oi-Pr)4,
TBHP
OH
O
92% ee
OH
(–)-DET,
Ti(Oi-Pr)4,
TBHP
OH
O
>90% ee
epoxidationSharpless asymmetric
18

19. epoxidationSharpless asymmetric
O
OH
TBHP
iPrO2C
CO2iPr
OH
OH
(+)-DIPT
EtO2C
CO2Et
OH
OH
(–)-DET
19

20. epoxidationSharpless asymmetric
OH
allylic alcohol
20

21. E
OO
O
Ti
O
O O
O
O
Ti
O
O
CO2Et
CO2Et
iPr
iPr
EtO
t-Bu
R
epoxidationSharpless asymmetric
21

22. R3
R1
R2
OH
D-(–)-DET
unnatural isomer
“O”
“O”
D-(+)-DET
natural isomer
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
mnemonic
predictive
22

23. left hand
R1
R2 R3
OH
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
for “O” on top or on
your kNuckles you
use Negative (–)-DET
for “O” on bottom or
on your Palm you
use Positive (+)-DET
23

24. ©Jackal1@flickr
O
N•HCl
CF3
J. Org. Chem., 1988, 53, 4081 &
J. Am. Chem. Soc., 1987, 109, 5165
(R)-fluoxetine
24

25. Ph OH
SAE
(+)-DIPT
TBHP
89%
>98%ee
Ph OH
O
Ph NHMe
O
CF3
in
total synthesis
chiral
catalysis
25

26. dihydroxylation
Sharpless asymmetric
Ph
Ph
Ph
Ph
OH
OH
Ph
Ph
OH
OH
98.8% ee >99.5% ee
K2OsO2(OH)4,
K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH,
H2O, 0°C,
(DHQD)2-PHAL (DHQ)2-PHAL
26

27. dihydroxylation
Sharpless asymmetric
ligands
N
H
O
N
MeO
Et
N
H
O
N
OMe
Et
NN
(DHQD)2-PHAL
N
H
O
N
OMe
N
H
O
N
MeO
N N
Et Et
(DHQ)2-PHAL
27

28. SAD
H
MS
L
OsO4
(DHQ)2PHAL
OsO4
(DHQD)2PHAL
mneumonic
attractive area - attracts
aromatic substituents or
large, hydrophobic
aliphatic groups
28

29. ©Jack Scott, Department of Biological Sciences, University of Alberta
O
O
Et
exo-brevicominTetrahedron Lett., 1993, 34, 5031
29

30. O
O
Et
OsO4, K3Fe(CN)6,
K2CO3, MeSO2NH2,
t-BuOH, H2O, 0°C,
(DHQD)2-PHAL
O
O
Et
HO
OH
95% ee
TsOH
O
O
Etin
total synthesis
SAD
30

31. R R
O
B
F
F
F
δ+++
nuc
Lewis acid catalysis
fast
31

32. ligandsbis(oxazoline)
Box ligands
N
O
N
O
R R
32

33. N
OH
H2N
HO
R R
O O
H
H
NC CN HO2C CO2H
amino acidsfrom
Box ligands
33

34. O
O
St-Bu
OSiMe3
N
O
N
O
t-Bu t-Bu
Cu
TfO OTf
85%
regioselectivity 98:2
97% ee
86% de
O
St-Bu
OHO
in the
aldol reaction
chiral catalysis
34

35. in the
aldol reactionchiral catalysis
N
O
N
O
t-Bu t-Bu
Cu
O O
35

36. N
O
N
O
t-Bu t-Bu
Cu
O O
St-Bu
Me3SiO
36

37. phoboxazole B
Angew. Chem. Int. Ed., 2000, 39, 253
J. Am. Chem. Soc., 2000, 122, 1003
O
BrMeO
HO
H
HO
OMe
O
N
O
N
O
O
O
O
H O H H
H
OH
H
©rei-san@flickr
37

38. Ph
O
N CHO
St-Bu
OSiMe3
N
O
N
O
Ph Ph
Sn
TfO OTf
91%
94% ee
Ph
O
N
OH
t-BuS O
in
total synthesis
chiral catalysis
38

39. in
Diels-Alder reactionschiral catalysis
NO
OO
N
O
N
O
t-Bu t-Bu
Cu
TfO OTf
cat 5-10mol%
92%
97%ee
H
O N
H
O
O
39

40. in
Diels-Alder reactionschiral catalysis
Me Me
OO
Cu
N N
OO
O N MeMe
Me
Me
Me
2+
bidentate
substrate
40

41. reactions
in
hetero-Diels-Alderchiral catalysis
H
OEt
O
O
cat 2-5mol%
72%
97%ee
O
CO2Et
H
O
H
H
O
OH
i. KOH
ii. HCl
N
O
N
O
t-Bu
t-Bu
Cu
TfO OTf
*
*
41

42. Cu
N N
OO
2+
O O
HEtO
reactions
in
hetero-Diels-Alderchiral catalysis
42

43. ©CDC
O
CO2H
OH
OH
O Et
(+)-ambruticin
J. Am. Chem. Soc., 2001, 123, 10772
43

44. coccidioidomycosis
O
CO2H
OH
OH
O Et
©Dr J.W. Rippon
44

45. in
total synthesis
chiral catalysis
TBSO
OBn
TBDPSO
O
H
N
Cr
O
O
Cl
neat, 25°C
64%
97%ee
O
OBn
OTBDPS
TBSO
O
CO2H
OH
OH
O Et
45

46. in
total synthesis
chiral catalysis
O
CO2H
OH
OH
O Et
N
Cr
O
O
TBDPSO H
O
TBSO
OBn
46

47. O
CO2H
OH
OH
O Et
in
total synthesis
chiral catalysis
TESO
Et
OTBS
O
H
Me
ent-cat
neat, 25°C
64%
97%ee
O
Et
OTBS
TESO
Me
47

48. organocatalysis
©Meredith_Farmer@flickr
48

49. reactionin the aldol
H
O
H
O
cat (10%)
H
O OH
88%
anti / syn 3 / 1
97% ee
N
H
O
OH
L-proline
organocatalysis
49

50. aldo
proline-catalysed
mechanism of
N
H
O
OH
N
O
OH
N
O
OH
N
O
O
H
H
O
H
H
OH
H
O
H
O
50

51. O H
N
O
H
H
H
O
transition state?
51

52. O
H
MOMO
O
Cl
Cl
Cl
Cl
Cl
Cl
N
N
H
•TFA
O
Ph
(5mol%)
94%
93%ee
O
H
MOMO
Cl
enamine
catalysis
52

53. enamine
general
mechanism
N
N
R2
R1
O
R2
N
N
H
O
Ph
R1
O
Ph
N
N
R2
R1
O
Ph
N
N
R2
R1
O
Ph
E
N
N
R2
R1
O
Bn
E
R1
O
R2
E
53

54. ©aussiegall@flickr
(–)-brasoside
J. Am. Chem. Soc., 2005, 127, 3696
O
H
H
Me O O OH
OH
OH
HO
O
O
54

55. total synthesis
enamine catalysis in
O
OMes
N
H
CO2H
D-proline
(0.4eq)
PhN=O
O
OMes
OPhHN
OMes
HO
CO2Me
Wittig
reaction
56%
(2 steps)
O2C
O
NH
N
R
Ph
O
H
H
O O OH
OH
OH
HO
O
O
55

56. O
H
H
O O OH
OH
OH
HO
O
O
total synthesis
enamine catalysis in
H
O
OBn
H
O
OBn
N
H
CO2H
78%
98%ee
H
O
OBn
OH
OBn
O OBn
OBn
TMSO
RO
OBn
56

57. R1
O
R2
nuc
R1
O
R2
nuc
LA
LA
LUMO-lowering
catalysis
fastslow
57

58. R1
N
R2
nuc
R1
O
R2
nuc
N
H
LUMO-lowering
catalysis
fastslow
catalysis
iminium
58

59. Ph
O
BnO OBn
O O
N
N
H
CO2HBn
cat. (10%),
neat, rt, 165h Ph
CO2Bn
BnO2C
O
86%
99% ee
catalysis
iminium ion
59

60. catalysis
iminium ion
N
N CO2H
H
CO2Bn
BnO
O
N
N CO2H
H
CO2Bn
CO2Bn
H
60

61. O
OH
O
Ph O
(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955©Rosebud 23@flickr
61

62. O
OH
O
Ph O
(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955
62

63. in total synthesis
O
OH
O
Ph O
O
OH
O
Ph
O
N
H
H
N
Ph
Ph
CO2H
96%
82%ee
catalysisiminium
63

64. O
HR1
O
HR1
LA
O
HR1
H
NN
H
X
R2 R3
δ+
unactivated Lewis acid H-bonding
hydrogen
bonding catalysis
64

65. N
S
O
(5mol%)
TMSCN
87%
97%ee N
S
OTMSNC
H
N
N
H
N
H
NHPr
t-Bu S
O
catalysis
H-bond
65

66. O
O
P
O
O H
phosphoric
acids
chiral
66

67. proton in heteroDiels-Alder reaction
chiral
N
Cl
HO
OTMS
MeO
OMe
(3mol%)
90%
97%ee
N
O
OMe
OH
Cl
O
O
P
O
O
N
H
67